Metalloprotease meprin β is activated by transmembrane serine protease matriptase-2 at the cell surface thereby
Felix Jäckle1, Frederike Schmidt1, Rielana Wichert1
1Unit for Degradomics of the Protease Web, Institute of Biochemistry, University of Kiel, 24118 Kiel, Germany.
Abstract:
Increased expression of metalloprotease meprin β is associated with fibrotic syndromes and Alzheimer's disease (AD). Hence, regulation of meprin activity might be a suitable strategy for the treatment of these conditions. Meprin β is a type 1 transmembrane protein, but can be released from the cell surface by ectodomain shedding. The protease is expressed as an inactive zymogen and requires proteolytic maturation by tryptic serine proteases. In the present study, we demonstrate, for the first time, the differences in the activation of soluble and membrane bound meprin β and suggest transmembrane serine protease 6 [TMPRSS6 or matriptase-2 (MT2)] as a new potent activator, cleaving off the propeptide of meprin β between Arg(61) and Asn(62) as determined by MS. We show that MT2, but not TMPRSS4 or pancreatic trypsin, is capable of activating full-length meprin β at the cell surface, analysed by specific fluorogenic peptide cleavage assay, Western blotting and confocal laser scanning microscopy (CLSM). Maturation of full-length meprin β is required for its activity as a cell surface sheddase, releasing the ectodomains of transmembrane proteins, as previously shown for the amyloid precursor protein (APP).
Insights
Researchers identified transmembrane serine protease 6 (TMPRSS6) as a novel activator for meprin β, a metalloprotease linked to fibrotic syndromes and Alzheimer's disease (AD). This finding offers new therapeutic strategies for treating these conditions.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Meprin β expression is linked to fibrotic syndromes and Alzheimer's disease (AD).
- Meprin β is a metalloprotease synthesized as an inactive zymogen requiring proteolytic activation.
- Understanding meprin β activation is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the differential activation of soluble and membrane-bound meprin β.
- To identify novel activators of meprin β.
- To explore the role of meprin β maturation in its sheddase activity.
Main Methods:
- Mass spectrometry (MS) for propeptide cleavage site determination.
- Fluorogenic peptide cleavage assay to measure protease activity.
- Western blotting and confocal laser scanning microscopy (CLSM) for protein analysis and localization.
Main Results:
- Transmembrane serine protease 6 (TMPRSS6, also known as matriptase-2 or MT2) was identified as a potent activator of meprin β.
- MT2 cleaves the meprin β propeptide between Arg61 and Asn62, enabling its maturation.
- MT2, but not TMPRSS4 or pancreatic trypsin, activates full-length meprin β at the cell surface.
- Activated meprin β functions as a cell surface sheddase, releasing ectodomains of transmembrane proteins like APP.
Conclusions:
- TMPRSS6 is a novel and potent activator of meprin β.
- The maturation of meprin β by TMPRSS6 is essential for its function as a cell surface sheddase.
- Targeting meprin β activation presents a potential therapeutic avenue for fibrotic syndromes and Alzheimer's disease.
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